Ritonavir



Better Known as: Norvir (Kaletra when used in combination with Lopinavir)

 * Marketed By: Abbott Laboratories


 * Major Indication: Human Immunodeficiency Virus Infection


 * Drug Class: HIV Protease Inhibitor
 * Date of FDA Approval (Patent Expiration): 1996 (2013)


 * U.S. 2009 Sales: $310 Million
 * Importance: It is a powerful HIV Protease inhibitor. It is a major component of most HIV combination therapies because of its potent inhibition capacity of CYP3A4, increasing the bioavailability of other viral inhibitors.
 * See Pharmaceutical Drugs for more information about other drugs and disorders.

Mechanism of Action
When HIV infects a host, it directs the synthesis of several polyproteins. The maturation of the virus to its infectious form requires that these polyproteins be cleaved to their component proteins by HIV Protease. The subunits of HIV Protease come together to form a catalytic tunnel capable of binding the nascent peptides and cleaving them into their mature form. Buried within this tunnel lies two Asp-Thr-Gly conserved sequences, which contain the catalytic Asp residues. These catalytic Asp residues carry out the hydrolytic cleavage of the viral polyproteins. Ritonavir binds very precisely to these conserved sequences within the HIV Protease tunnel, preventing the nascent polyproteins from entering. Unable to actively cleave the nascent proteins into their functional form, HIV is unable to mature and proliferate, allowing the patients immune system to fight off the infection more easily.

Despite its ability to inhibit HIV Protease, Ritonavir is primarily used in combination therapies to inhibit the metabolizing enzyme, cytochrome P4503A4 (CYP3A4). Ritonair binds with high affinity to CYP3A4, inhibiting it. Since it is this enzyme which is responsible for metabolizing the other HIV Protease inhibitors, Ritonavir's inhibition of CYP3A4 increases the bioavilaibility of other antiviral medications.

Drug Resistance
The biggest difficulty with treating HIV is the rapidity at which it mutates and becomes resistant to treatments. To view a comprehensive and interactive analysis of the mutations which confer drug resistance to HIV Protease, See: HIV Protease Inhibitor Resistance Profile